Origin, virological features, immune evasion and intervention of SARS-CoV-2 Omicron sublineages

Abstract

Recently, a large number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants continuously emerged and posed a major threat to global public health. Among them, particularly, Omicron variant (B.1.1.529), first identified in November 2021, carried numerous mutations in its spike protein (S), and then quickly spread around the world. Currently, Omicron variant has expanded into more than one hundred sublineages, such as BA.1, BA.2, BA.2.12.1, BA.4 and BA.5, which have already become the globally dominant variants. Different from other variants of concern (VOCs) of SARS-CoV-2, the Omicron variant and its sublineages exhibit increased transmissibility and immune escape from neutralizing antibodies generated through previous infection or vaccination, and have caused numerous re-infections and breakthrough infections. In this prospective, we have focused on the origin, virological features, immune evasion and intervention of Omicron sublineages, which will benefit the development of next-generation vaccines and therapeutics, including pan-sarbecovirus and universal anti-CoV therapeutics, to combat currently circulating and future emerging Omicron sublineages as well as other SARS-CoV-2 variants.

Fig. 1

Emergence and spread of Omicron sublineages. a Emerging timeline for Omicron sublineages. Earliest date for each sublineage is from cov-lineages.org (continuously updated). b Prevalence of Omicron sublineages and other variants in India, the United Kingdom, the United States, and South Africa based on all sequences available on GISAID over the past 6 months. c Schematic representation of the genomic domains of SARS-CoV-2 with mutations in Omicron sublineages. PLpro (NSP3), papain-like protease; 3CLpro (NSP5), 3C-like protease; RdRp (NSP12), RNA-dependent RNA polymerase

Fig. 2

Structural comparations of ACE2-RBD interface and bebtelovimab (LY-CoV1404)-RBD interface in S protein of Omicron sublineages. a Superposition of complex structures of SARS-CoV-2 spike with human ACE2 (hACE2) receptor (PDB entry 7FEM) and spike RBD domain with LY-CoV1404 neutralizing antibody (PDB entry 7MMO) are shown on the left panel. RBD-LY-CoV1404 interface (PDB entry 7MMO) and RBD-hACE2 interface (PDB entry 6M0J) are enlarged in the middle panel and plotted on the RBD surface in the right panel. SARS-CoV-2 S protein is colored in medium slate blue, light coral and dark sea green for three protomers, respectively. Spike RBD domain alone is colored in medium slate blue. The hACE2 and its interface are colored in burlywood. LY-CoV1404 and its interface are colored in coral. Interface edges of LY-CoV1404 and hACE2 on RBD surface are indicated by white dotted line or blue dotted line, respectively. b–e Structural comparison of LY-CoV1404 binding interface, hACE2 binding interface and point mutations on spike RBD surface in Omicron sublineages, including BA.1 (PDB entry 7WPB) (b), BA.2 (PDB entry 7UB0) (c), BA.3 (predicted by SWISS-MODEL) and (d), BA.4/BA.5 (predicted by SWISS-MODEL) (e). RBD surface, interface edges of LY-CoV1404 and hACE2 are shown as (a). Point mutations of Omicron sublineages are colored in red, dark red or firebrick, and labeled accordingly